Neurodegenerative disease encompasses a range of seriously debilitating conditions including Parkinson's disease, ALS ("Lou Gehrig's disease"), multiple sclerosis, Huntington's disease, Alzheimer's disease and the like. These conditions are characterized by a gradual but relentless worsening of the patient's condition over time. The mechanisms and causes of these diseases are becoming better understood and a variety of treatments have been suggested.
A recent summary of the state of understanding of Parkinson's disease is provided by Marsden, C. D., in "Review Article--Parkinson's Disease" Lancet (Apr. 21, 1990) 948-952. As that review points out, dopamine deficiency was identified as a key characteristic of Parkinson's disease, and the destruction of the dopaminergic nigrostriatal pathway paralleled dopamine depletion in Parkinson's patients.
Rapid development of Parkinson's-like symptoms in a small population of illicit drug users in the San Jose, California area was linked to trace amounts of a toxic impurity in the home-synthesized drugs. Subsequent studies in animal models, including monkeys, demonstrated that 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was the cause of the Parkinson's-like symptoms which developed in the illicit drug users, as reported by J. W. Langston et al., in "Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis" Science (Feb. 25, 1983) 219, 979-980. These early findings and the many studies that they stimulated led to the development of reliable models for Parkinson's disease, as reported by Heikkila, R. E., et al., in "Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice" Science (Jun. 29, 1984) 224:1451-1453; Burns, R. S., et al., in "A Primate Model of Parkinsonism . . . " Proc. Natl. Acad. Sci USA (1983) 4546-4550; Singer, T. P., et al., "Biochemical Events in the Development of Parkinsonism . . . " J. Neurochem. (1987) 1-8; and Gerlach, M. et al., "MPTP Mechanisms of Neurotoxicity and the Implications for Parkinson's Disease" European Journal of Pharmacology (1991) 273-286. These references and others describe studies to help explain the mechanism of how the administration of MPTP to animals gives rise to motor defects characteristic of Parkinson's disease. They clearly indicate that MPTP was the cause of the Parkinson's-like symptoms that developed in the humans that had used the tainted illicit drugs and that similar motor deficits were found in other primates and other test animals which had been dosed directly with MPTP. They further point out that the administration of MPTP induces a marked reduction in the concentration of dopamine in the test subjects. Loss of dopamine in certain brain regions is well associated with Parkinson's disease.
These findings have led to the development of an assay for anti-Parkinson's agents. In this assay, test animals are given an amount of MPTP adequate to severely depress their dopamine levels. Test compounds are administered to determine if they are capable of preventing the loss of dopamine in the test animals. To the extent that dopamine levels are retained, a compound can be considered to be an effective agent for slowing or delaying the course of Parkinson's disease.
The present invention concerns eleven benzamides and their use as active pharmaceutical agents. These benzamides, N-(carboxymethyl) 4-nitrobenzamide (CPI37), N-phenyl trimethylacetamide (CPI1009), N-isobutyl 3,5-dinitrobenzamide (CPI1064), N-tert-butyl benzamide (CPI1010), N-tert-butyl 4-nitrobenzamide (CPI1020), N-tert-butyl 4-bromobenzamide (CPI1036), N-tert-butyl 4-methylbenzamide (CPI1039), N-tert-butyl 4-cyanobenzamide (CPI1043), N-tert-butyl 3,5-dinitrobenzamide (CPI1049), N-tert-butyl-N-methyl 4-nitrobenzamide (CPI1052), and N-tert-butyl 4-nitrobenzthioamide (CPI1057), are known chemical compounds. They are depicted structurally in Table 1. In this table and elsewhere in this specification, the various benzamides are accompanied by internal compound designation numbers. These numbers are provided to help keep straight the identities of these several closely related materials. Chemical Abstracts or Beilstein Registry identification numbers are also provided in Table 1.
TABLE 1 ______________________________________ Int. Chem. Ident. Abstract No. Structure No. ______________________________________ 1010 ##STR1## 5894-65-5 1020 ##STR2## 42498-30-6 1043 ##STR3## Beilstein Reg. No. 3250293 1036 ##STR4## 42498-38-4 37 ##STR5## 2645-07-0 1052 ##STR6## 54284-31-0 1057 ##STR7## 34496-27-0 1009 ##STR8## 6625-74-7 1049 ##STR9## 56808-99-2 1064 ##STR10## 1039 ##STR11## 42498-32-8 ______________________________________
While these compounds are known, their utility heretofore has generally been as intermediates in chemical syntheses or in fields unrelated to the present invention. Slight structural changes yielded large differences in efficacy and toxicity. The vast majority of benzamide compounds tested had little or no activity in our screens. However, there are reports of biological activity for other, structurally different benzamides. These reports include:
El Tayar et al., "Interaction of neuroleptic drugs with rat striatal D-1 and D-2 dopamine receptors: a quantitative structure--affinity relationship study" Eur. J. Med. Chem, (1988) 23:173-182; PA1 Monkovic et al., "Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides" Eur. J. Med. Chem. (1989) 24:233-240; PA1 Banasik et al., "Specific inhibitors of poly(ADP-Ribose) synthetase and mono(ADP-ribosyl)transferase" J. Biol. Chem. (1992) 267:1569-1575; PA1 Bishop et al., "Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D.sub.2 receptors" J. Med. Chem. (1991) 34:1612-1624; PA1 Hogberg et al., "Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners" J. Med. Chem. (1991) 34:948-955; PA1 Katopodis et al., "Novel substrates and inhibitors of peptidylglycine .alpha.-amidating monooxygenase" Biochemistry (1990) 29:4541-4548; and PA1 Rainnie et al., "Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal" Science (1994) 257:689-690. PA1 N-(carboxymethyl) 4-nitrobenzamide, PA1 N-phenyl trimethylacetamide, PA1 N-isobutyl 3,5-dinitrobenzamide, PA1 N-tert-butyl benzamide, PA1 N-tert-butyl 4-nitrobenzamide, PA1 N-tert-butyl 4-bromobenzamide, PA1 N-tert-butyl 4-methylbenzamide, PA1 N-tert-butyl 4-cyanobenzamide, PA1 N-tert-butyl 3,5-dinitrobenzamide, PA1 N-tert-butyl-N-methyl 4-nitrobenzamide, and PA1 N-tert-butyl 4-nitrobenzthioamide. PA1 N-(carboxymethyl) 4-nitrobenzamide, PA1 N-phenyl trimethylacetamide, PA1 N-isobutyl 3,5-dinitrobenzamide, PA1 N-tert-butyl benzamide, PA1 N-tert-butyl 4-nitrobenzamide, PA1 N-tert-butyl 4-bromobenzamide, PA1 N-tert-butyl 4-methylbenzamide, PA1 N-tert-butyl 4-cyanobenzamide, PA1 N-tert-butyl 3,5-dinitrobenzamide, PA1 N-tert-butyl-N-methyl 4-nitrobenzamide, and PA1 N-tert-butyl 4-nitrobenzthioamide PA1 N-tert-butyl benzamide (CPI1010), PA1 N-tert-butyl 4-nitrobenzamide (CPI1020), PA1 N-tert-butyl 3,5-dinitrobenzamide (CPI1049), PA1 N-tert-butyl 4-nitrobenzthioamide (CPI1057), and PA1 N-isobutyl 3,5-dinitrobenzamide (CPI1064) are preferred. PA1 Of these, N-tert-butyl benzamide (CPI1010) and PA1 N-tert-butyl 4-nitrobenzamide (CPI1020)